December 14, 2001

Vanderbilt search for inflamed gene nets $10 million

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Participating in the study are, from left, seated, Earl Ruley and Jacek Hawiger. Standing, left to right, Shawn Levy, Mark Hughes, Luc VanKaer, and Gene Oltz. (photo by Dana Johnson)

Vanderbilt search for inflamed gene nets $10 million

A five-year, $10 million Research Program Project Grant landed by the department of Microbiology and Immunology will fund a discovery-driven multi-pronged effort to identify new genes that mediate immune inflammatory response.

Dr. Jacek Hawiger, Oswald T. Avery Professor and Chair of Microbiology and Immunology, will direct the National Heart Lung and Blood Institute funded program project titled “Functional Genomics of Inflammation,” which will involve a tightly knit organization of interacting laboratories and core research facilities.

“I think we have a novel and synergistic approach to inflammation as the major mechanism of multiple diseases,” Hawiger said. “None of us could accomplish this alone.”

Inflammation is a response of blood cells and plasma proteins of the immune system to foreign organisms and substances, or what the body recognizes as an abnormal cell makeup. The inflammatory response underlies a variety of human diseases, including pneumonia, arthritis, hepatitis, atherosclerosis, encephalitis, and such autoimmune diseases as Type 1 diabetes, lupus, and multiple sclerosis, among others.

About 250 genes are currently known to encode mediators or suppressors of inflammation. But, according to Hawiger, there are probably two to three times that number as yet unidentified. Using mice as a model, the investigators will try to identify genes by looking at gene products, or proteins, and how they function in the inflammatory response.

“This program is really about the hunt for ‘inflamed genes,’” he said, “using a combination of blood cell-based genomics and proteomics.”

Leaders from four primary projects and three core facilities will work in concert to accomplish the program’s goals. Project 1, led by H. Earl Ruley, Ph.D., professor of Microbiology and Immunology and Ingram Professor of Cancer Research—and associate director of the program—will focus on screening a library of more than 600 embryo-derived stem (ES) cell clones in which genes of potential importance in blood cell inflammatory response have been disrupted.

The DNA Microarray Core, headed by Shawn E. Levy, Ph.D., research assistant professor of Molecular Physiology and Biophysics, will develop DNA chips containing sequences derived from each disrupted gene in the mutant ES cell library in addition to sequences from 15,000 known mouse genes. These arrays will be used for comparing gene expression profiles of unstimulated, or resting, cells with profiles of cells stimulated with various pro-inflammatory agonists.

After extensive analysis of the expression profiles, the investigators will select certain genes for transmission to the germline of a mouse in order to produce offspring with a deficiency of that specific gene.

Hawiger expects that some of the gene deficient mice will have an abnormal inflammatory response. The researchers will assess the effects on specific blood cell types.

The Animal Models Core facility, under the direction of Luc Van Kaer, Ph.D., associate professor of Microbiology and Immunology and Howard Hughes Medical Institute Investigator, will evaluate the animals generated in Project 1 for successful transmission of the targeted gene. If the mutation is non-lethal, the Core will establish a breeding colony of homozygous mutant animals and screen them for changes in blood cell numbers and cellular responses. Depending on which cell type has incurred altered function, further characterization of the mutation’s effect will be the responsibility of one of three other project teams.

Project 2, led by Hawiger, will focus on phagocytes—granulocytes, monocytes, macrophages, dendritic, and mast cells—which are the first line of defense in inflammatory response. Van Kaer will lead Project 3, investigating the role of mutant genes in T lymphocyte development, activation, and differentiation, as well as T lymphocyte-based inflammation. Project 4, directed by Eugene M. Oltz, Ph.D., associate professor of Microbiology and Immunology, will examine how mutated inflammatory response genes affect B lymphocyte differentiation, activation, and function.

These efforts will lead to new animal models of either attenuated or heightened inflammatory response. The Bioinformatics Core, under the direction of Jason H. Moore, Ph.D., assistant professor of Molecular Physiology and Biophysics, will integrate all information from the genotype- and phenotype-oriented projects and cores into a relational database system accessible to all the project teams.

An Administrative Core overseen by Hawiger will assure the exchange of information, quality control data, and reagents to be shared with other investigators at Meharry Medical College and in the general scientific community. The Web site will facilitate the exchange of information among the program’s research units and the academic community.

An annual one-day retreat focused on “Inflamed Genes” and sponsored by the program is planned. “We hope that new discoveries by the program’s researchers will allow us to identify previously unappreciated targets for anti-inflammatory therapy and to write a new authoritative ‘state of the science’ book on the genomics and proteomics of inflammation,” Hawiger said.

Other co-investigators and consultants involved in the projects are Dean W. Ballard, Ph.D., professor of Microbiology and Immunology; Mark Boothby, Ph.D., associate professor of Microbiology and Immunology; Dr. Robert D. Collins, John L. Shapiro Professor of Pathology; Wasif N. Khan, Ph.D., assistant professor of Microbiology and Immunology; Andrew J. Link, Ph.D., Ingram Assistant Professor of Cancer Research; Dr. Xue-Yan Liu, research instructor of Microbiology and Immunology; and Dr. Derya Unutmaz, assistant professor of Microbiology and Immunology.

The Internal Advisory Board will provide counsel and scientific expertise for the implementation and ongoing review of the goals and objectives of the program. Members of the board include Brigid L. M. Hogan, Ph.D., FRS, Hortense B. Ingram Professor of Molecular Oncology and Howard Hughes Medical Institute Investigator; Shirley Russell, Ph.D., professor and chair of Microbiology at Meharry Medical College; Dr. John H. Exton, professor of Molecular Physiology and Biophysics and Howard Hughes Medical Institute Investigator; Dr. Douglas E. Vaughan, C. Sidney Burwell Professor of Medicine and director of the Division of Cardiovascular Medicine; Dr. Robert J. Coffey, Jr., Ingram Professor of Cancer Research; and Dr. James W. Thomas, II, professor of Medicine and director of the Division of Rheumatology and Immunology.